Early studies focused on septic shock pathophysiology (Am J Physiol 1988; Chest, 1990), the role of endotoxemia (J Clin Invest 1989; J Exp Med, 1989; Chest. 1991; N Engl J Med, 1993; Infect Immun 1996), and the efficacy of various anti-endotoxin therapies (Antimicrob Agents Chemother 1989) including lipid A analogs (J Clin Invest 1987; Pharm Res 1990) and antibodies (JAMA, 1993; J Infect Dis, 1994). Nitric oxide (NO) was examined as an important mediator of septic shock (Crit Care Med, 1993; JAMA 1996). Non-selective NO synthase inhibitors were found to be sometimes toxic and never beneficial (J Exp Med 1992; Crit Care Med 1998; Am J Respir Crit Care Med 1998). Normal volunteers challenged with endotoxin were shown to release increased amounts of NO. Although ibuprofen blocked endotoxin-induced increases in NO production, blood pressure was unaffected, suggesting that other mechanisms compensated to maintain vasodilation (J Pharmacol Exp Ther 1999). Severity of illness (risk of death) was found to influence the therapeutic efficacy of anti-inflammatory agents in septic shock (Am J Respir Crit Care Med 2002). This finding was used by the FDA to re-analyze the PROWESS trial of rhAPC (Xigris) and led to initial approval only for patients with a high risk of death. The lack of rhAPC efficacy in patients with a low risk of death was confirmed in the ADDRESS trial. The administration of L-arginine without or with N-acetylcysteine in a canine model of septic shock was found to be harmful (Crit Care Med 2006). L-arginine is a common component of immunonutrition formulas that are marketed for use in critically ill patients. Our canine septic shock model was redeveloped to better balance animal welfare and scientific relevance. Both specific and supportive titrated therapies routinely used in septic patients were fully integrated into the model to provide a more realistic setting to evaluate therapies for sepsis (Am J Physiol Heart Circ Physiol 2007). Whether risk of death altered the effects of hydrocortisone was invested in a mouse model of E. coli pneumonia (Intensive Care Med 2008). Intra-aortic balloon counterpulsation was demonstrated to prolong survival in a hypodynamic canine model of Staphylococcus aureas pneumonia induced septic shock (Crit Care Med 2009). This result suggests that counterpulsation support of left ventricular function might improve survival in episodes of septic shock associated with compromised cardiac output. A low cardiac output is seen in 10 to 20 percent of adults and up to 50 percent of children with septic shock. The U.S. Critical Illness and Injury Trials Group (USCIITG) was founded to create a clinical research framework that can reduce the barriers to investigation (http://www.massgeneral.org/research/researchlab.aspx?id=1262). USCIITG provides an annual venue for systematic review and strategic planning that will include framing the research agenda, and raising awareness for the value of acute care research (Crit Care Med 2009). A meta-analysis of bundled care for septic shock demonstrated consistent and significant improvement in survival and antibiotic use. Use of other bundle components changed heterogeneously across studies, making their impact on survival uncertain (Crit Care Med 2010). SB203580, a p38 inhibitor, improved cardiac function but worsened lung injury and survival during E. coli pneumonia in mice (J Trauma 2010). Anthrax lethal toxin (LeTx)-induced shock was found to differ substantially from LPS challenge in rats. Fluids and vasopressors, standard approaches to septic shock, were harmful (Crit Care Med 2009). Notably, anthrax infection fails to induce NO synthase 2, due to a LeTx-mediated truncation of inflammatory signaling inside cells. Twenty-four hour edema (ETx) and lethal (LeTx) toxin infusions were investigated for 96 h in sedated canines receiving mechanical ventilation. Etx was much less lethal than LeTx, but increased mortality when added to equimolar LeTx challenges (J Infect Dis 2010). Heparin in a mouse model of E. coli pneumonia failed to improve lung injury or survival Crit Care Med 2011). A systematic review and meta-regression analysis of published animal studies showed that heparin improved survival with lipopolysaccharide or surgically-induced infection, but not monobacterial challenges. Corticosteroid regimens that activate both mineralocorticoid (MR) and glucocorticoid receptors (GR) consistently reverse vasopressor-dependent hypotension in septic shock, but have variable effects on survival. In a canine model of S. aureus pneumonia-induced septic shock, selective agonists of MR and GR were examined separately. Mineralocorticoid was only beneficial if given prophylactically, while glucocorticoid was most beneficial when given close to the onset of infection (Crit Care Med 2012). Staphylococcus enterotoxin B (SEB) can trigger a lethal super antigen-mediated cytokine storm that may contribute to the high mortality of S. aureas sepsis and also poses a threat as a potential bioweapon. Using an aerosolized-toxin, mouse model, the genome-wide effects of SEB are being examined in an effort to identify therapeutic targets. This project has revealed an intense, late interferon response that precedes death and appears to be Toll-like receptor independent. Both lymphocyte cytokine production and apoptosis, somewhat paradoxically, have been linked to death from sepsis. Nuclear receptor modulation of lymphocyte activation and apoptosis is being investigated as a means to quell early excessive inflammation, while preserving immune function later in severe sepsis (FASEB J abstract, 2011).